Aberrant Activation of p38 MAP Kinase-Dependent Innate Immune Responses Is Toxic to Caenorhabditis elegans

G3 : Genes - Genomes - Genetics
Hilary K CheesmanRead Pukkila-Worley

Abstract

Inappropriate activation of innate immune responses in intestinal epithelial cells underlies the pathophysiology of inflammatory disorders of the intestine. Here we examine the physiological effects of immune hyperactivation in the intestine of the nematode Caenorhabditis elegans. We previously identified an immunostimulatory xenobiotic that protects C. elegans from bacterial infection by inducing immune effector expression via the conserved p38 MAP kinase pathway, but was toxic to nematodes developing in the absence of pathogen. To investigate a possible connection between the toxicity and immunostimulatory properties of this xenobiotic, we conducted a forward genetic screen for C. elegans mutants that are resistant to the deleterious effects of the compound, and identified five toxicity suppressors. These strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1, and pmk-1), demonstrating that hyperstimulation of the p38 MAPK pathway is toxic to animals. To explore mechanisms of immune pathway regulation in C. elegans, we conducted another genetic screen for dominant activators of the p38 MAPK pathway, and identified a single allele that had a gain-of-function ...Continue Reading

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Citations

Nov 9, 2016·Nature Communications·Guang LiX Z Shawn Xu
Jan 23, 2019·PLoS Genetics·Nicholas D PetersonRead Pukkila-Worley
Apr 14, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wenwen ZhangJun Zheng
Oct 16, 2019·Proceedings of the National Academy of Sciences of the United States of America·James D NhanSean P Curran
Aug 10, 2020·Genes and Immunity·Bhoomi MadhuTina L Gumienny
Sep 7, 2018·Molecular Biology of the Cell·Francesca Di CaraRichard A Rachubinski
Jan 22, 2021·PLoS Pathogens·Siddharth R Venkatesh, Varsha Singh

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